Endoxifen (4-hydroxy-N-desmethyl tamoxifen or EDX) is known to be responsible for the overall effectiveness of tamoxifen in treating ER-positive breast cancer as it is a primary active metabolite of the prodrug tamoxifen converted by the cytochrome P450 2D6 (CYP2D6) isoform[62,63] For this reason, women diagnosed with genetically impaired CYP2D6 activity have been found to have a higher propensity for breast cancer recurrence upon tamoxifen treatment[64] Oral administration of EDX would be a way to treat those women lacking CYP2D6; however, the orally taken and thus systemically exposed EDX has been reported to induce numerous side effects such as hot flashes, vaginal atrophy, endometrial cancer and thromboembolic events {Gjerde, 2012 #313}[65-68]. In order to address these issues, the present invention contemplates the local, transdermal delivery of EDX to the breast by topical administration, which would minimize the systemic exposure of the drug[69], thereby potentially reducing the side effects from oral tamoxifen/EDX.
For EDX to be effectively delivered through the skin layers, the molecules must go through a multi-layered barrier. In particular, the stratum corneum (SC) is the most significant barrier that needs to be overcome to effectively deliver drugs by the topical route[70]. EDX is a highly hydrophobic small molecule with a partition coefficient (log P) of 6.01 at 25° C.[71]. As this log P value is far beyond the optimum range (between 1 and 3)[72-76] for efficient skin permeation, EDX itself cannot be efficiently translocated through the skin layer without the use of penetration enhancers[77].
Chemical penetration enhancers (CPEs), such as ethanol and sodium dodecyl sulfate (SDS), have been commonly used to enhance the skin permeability of therapeutic molecules that are otherwise skin impermeable[74]. However, significant irritation and adverse effects have been often observed because of skin dehydration and/or SC lipid disruption, which is typically proportional to penetration enhancement abilities[74,78]. To overcome the problem of skin irritation, polymeric micelles have been introduced as potential platforms for transdermal drug delivery due to their small size, skin permeability, biocompatibility, high drug and gene adaptability, and tunable surface functionality and release profiles[79-83]. Polymeric micelles are small, spherical particles (<200 nm in diameter) made up of polymer chains. The polymer chains of polymeric micelles are block copolymers (i.e., typically linear polymers that are composed of repeating blocks of two polymers that differ in hydrophilicity, charge or polarity). Some block copolymers that are amphiphilic block copolymers self-assemble into micelles when placed in an appropriate solvent. A few types of polymeric micelles prepared from monomethoxy poly(ethylene glycol)-poly(s-caprolactone) (MPEG-PCL) copolymers {Xue, 2012 #270}, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymers and methoxy-poly(ethylene glycol)-hexyl substituted polylactide block copolymers have been reported to be used for transdermal drug delivery of oridonin (anticancer), econazole nitrate (antifungal), and plasmids (with 3-galactosidase gene), respectively.
Self-assembled polymeric micelles have nanostructural features, such as their thermodynamic stability, size, and shape of self-assemblies, that can be widely manipulated depending on both amphiphilicity of materials and fabrication techniques. Self-assembly is a process in which a stable ordered ensemble of molecules is formed through the balancing of attractive and repulsive forces between amphiphiles at a concentration above the critical micelle concentration (CMC). [1] One of the most promising types of block copolymers capable of self-assembling is the dendron-coil (DC), [2] A DC is comprised of a flexible linear polymer dendronized at one end in which amphiphilicity can be engineered through the appropriate choice of hydrophilic and hydrophobic blocks. The highly branched, controlled molecular architecture of the dendron allows the unique properties of dendrimers such as monodispersity, precise control of peripheral functional groups, and multivalency to be integrated.[3]
Many groups have reported amphiphilic DCs and other dendron-based copolymers capable of self-assembling into a wide variety of morphologies.[2] Particularly, amphiphilic DCs containing a single hydrophobic peptide block and multiple hydrophilic blocks combined through mediation by a dendron have been shown to preferentially self-assemble into spherical micelles with sizes less than 100 nm.[4]
Over the past decade, significant advances have been made in the development of polymeric micelles to treat and detect cancer effectively[5] and various design strategies have been implemented to enhance cancer targeting.[6,7] The hydrophilic-lipophilic balance (HLB) between polymer chains is a crucial factor used to describe the self-assembly behavior of polymers and is strongly associated with the degree of micellar dissociation and blood circulation time augmenting the enhanced permeability and retention (EPR) effect. In addition, by controlling the HLB it has been shown that a variety of morphologies can be induced (e.g. vesicular, spherical, cylindrical micelles) via self assembly as a result of the interplay between thermodynamic forces.[8] A well-defined density of targeting ligands on the surface and their adopted geometry are also important to produce enhanced selective binding to cancer tissues as supported by recent studies on multivalent cancer targeting.[9,10] In this regard, a dendron, a segment of a dendrimer, is a unique material that not only retains the properties of its parent dendrimer (symmetry and monodispersity) but through distinctive chemical modifications of its focal point and periphery can be hybridized with other materials to create amphiphilic structures that self-assemble and exhibit unique biological responses[11].
In Oerlemans et al. 2010[5], the authors review research and clinical trials on polymeric micelles in anticancer thereapy. In Table 1 on page 2571, the review article reports that five micelle products for anticancer therapy had been investigated in clinical trials, one of which (Genexol-PM) has been granted FDA approval to be used in patients with breast cancer. In Table VII on page 2583, the review article lists various multifunctional micellar formulations, including a EGF-receptor-targeted PEG-b-PCL micelles labeled with 111In and a micellar formulation consisting of folate-conjugated PEG-b-PCL loaded with doxorubicin and SPIONS, that combine two or more the functions of targeting ligands, imaging agents and triggered release. At the end of its “Conclusion and Future Perspectives” section on page 2583, the authors state that “the versatility of micelle-based drug delivery and the large number of promising preclinical studies describing numerous approaches to optimize these nanomedicines will bring the development of a magic bullet a major step forward. Now it is time to bring this potential into clinical practice.”
Thus, there exists in the art a need for products and methods for the transdermal delivery of drugs to target cells.